A pure Cutaneous Rosai-Dorfman disease: case report and a review of the literature

Background: Cutaneous Rosai-Dorfman disease (CRDD) is a rare variant of benign histiocytic proliferative disorder limited to the skin. The underlying etiology is still unclear, but it had been claimed that infections, immunodeficiencies, and autoimmune disorders might have a role in the etiology of this disorder. The characteristic presentation of RDD is lymphadenopathy due to abnormal production and accumulation of histiocytes in lymph nodes; however, the extra-nodal areas could also be affected, such as cutaneous. Herein, we presented a 45-year-old Iranian woman presented with an atypical pure cutaneous Rosai Dorfman disease, in addition to a summarized list of atypical cases of RDD that are reported as pure cutaneous RDD with atypical presentation. Case presentation: Herein, we presented a 45-year-old woman who referred to us with an ulcerative nodule with a size of 5×5 cm on her buttock, gradually growing over one year. After the primary evaluations, a biopsy specimen was obtained, and histologic studies revealed a dense cellular infiltrate involving the dermis and the subcutis, which was composed of abundant sheets of large histiocytes with admixtures of lymphocytes, plasma cells, neutrophils, and eosinophils within their cytoplasm -known as the emperipolesis phenomenon. The immunohistochemistry staining was positive for S100 and CD68 and negative for CD1a. Conclusion: The diagnosis of CRDD was confirmed based on these histopathological findings.

R osai-Dorfman disease (RDD) is a rare disorder first described in 1965 by Destombes, and later in 1969, Rosai and Dorfman recognized it as a distinct entity coined as sinus histiocytosis with massive lymphadenopathy. (1,2)RDD is classified as the 'R group 'of histiocytosis disorders and categorized into three main categories: familial, cutaneous, and sporadic (the most common form)(3)Considering the rareness of the disorder, the exact etiology of RDD remains as yet obscure. However, some studies showed the association between this disorder and viral infections such as the human immunodeficiency viruses (HIV), herpes simplex virus ; and autoimmune disorders like systematic lupus erythematosus (SLE) and Crohn's disease (4,5). The basic pathology behind RDD is the abnormal accumulation of histiocytes in different tissues and organs; therefore, a wide range of presentations could occur based on the affected area. The isolated cutaneous manifestations without any nodal involvement and systematic features are categorized as CRDD forms of RDD. (6)CRDD is usually presented with painless, non-pruritic, slowly progressive nodules that are purely limited to the dermis and subcutaneous.
A thorough history taking and physical examination, then more evaluations such as excisional biopsy, can help to reach the diagnosis (4,6). The subacute clinical symptomatology alongside histopathological examinations and immunohistochemical studies will confirm the diagnosis of CRDD. The classic histologic finding in RDD is identified by finding many clusters of histiocyteswith hypochromic nuclei, and phagocytosed lymphocytes, plasma cells, neutrophils within their cytoplasm, and the characteristic immunohistochemical staining analysis for CRDD is reported as positive cytoplasmic and nuclear S100 with CD68 and CD14 accompanied by negative CD1a and CD207 (7,8). Commonly, RDD is a benign and uncomplicated disease that may have spontaneous remissions; therefore, observation is a reasonable choice of treatment in most cases, but the most effective therapy in the unifocal forms of the disease is surgical excision of the histiocytic lesion (6,9). Histiocytosis based on its type, may mimic a wide variety of dermatologic disorders, so getting more familiar with different clinical presentations (10, 11) helps us to easier and better approach to the patients. In this regard, reporting different clinical presentations of histiocytosis especially atypical ones are of great value. Herein we present a 45-year-old patient with a solitary nodule growing gradually on the patient's lower extremity without lymphadenopathy or any systematic symptoms.Also, we have a summarized list of atypical cases of RDD that are reported as pure cutaneous RDD with atypical presentation (table1).

Case presentation
A 45-year-old woman was referred to our hospital presented with an ulcerative indurated lesion located on her buttock. The lesion started to appear almost a year ago as a single popular lesion which gradually enlarged to a round erythematous nodule with a progressive growth over the last two months. She denied any history of pain, itchy sensations, and secretion from the lesion; also, patient did not experience any constitutional symptom such as malaise, weight loss, and fever over the past year. The patient was in good health and had no significant past medical history or family history of malignancies.
The physical examination revealed a round reddish-yellow mass approximately 5 cm in diameter located above the right buttock's gluteal fold, and the ulceration was without any evidence of necrosis or bleeding; the rest of her physical examination and her laboratory evaluations were unremarkable. Before this admission, she was treated with antibiotics under the impression of the abscess by another clinician, which did not have any significant effect on her situation. We obtain a biopsy specimen from the lesion, and a histopathological study followed by immunohistochemical (IHC) staining for the patient. The histopathologic analysis reported a dense cellular infiltration involving the dermis and the subcutis with associated sclerosis.
The infiltrate is composed of predominantly of large epithelioid histiocytes with pale eosinophilic cytoplasm. Admixed with these histiocytes are small lymphocytes, plasma cells, neutrophils, and eosinophils (fig 2). Some histiocytes contain intact lymphocytes (emperipolesis) (fig 3a, b). Lymphocytic aggregations in addition to a mild vascular proliferation were also seen. The overlying epidermis shows acanthosis with ulcer (fig1). In IHC, the histiocytes showed expression of S100, CD68 and CD45((figs 4,5,6) and were negative for CD1a.

Discussion
The most typical presentation of Rosai Dorfman disease (RDD) is lymphadenopathy; however, extra-nodal sites were also reported to be affected in less than half of the cases.(12)Skin as the most common site is involved in about 10% of RDD cases, but the isolated extra-nodal presentations of RDD are extremely rare -only 3 percent of all reported cases are purely cutaneous RDD.(6)Usual presentations of pure cutaneous RRD, are non-specific dark red or yellow papulonodular lesions or plaques that are commonly located in the face, trunk, and upper and lower limbs.(13) Therefore, our patient presentation is an atypical form of pure CRDD; a solitary ulcerative nodule located on the lower extremity.
From an epidemiological point of view, this disease affects all age groups, sexes, and races, but the demographic pattern and ethnicity distribution differ between CRDD and systemic RDD cases. Systematic RDD is more common in younger patients (mean age of onset 20.6 years) predominantly in men (4:1 ratio) with African ethnicity; on the contrary, CRDD usually affects older individuals (mean age of onset 43.5 years) with a female predominance (2:1 ratio) and is mainly reported in patients with Asian and Caucasian ethnicity (12,14). Compatible with these patterns, our patient was an Iranian woman whose disease onset was at the age of 44. RDD is known as a benign disorder which rarely has a fatal outcome; patients mostly either have a complete spontaneous remission or have an suitable response to the required treatment (9,15). The therapeutic strategics are decided based on the patients' clinical circumstances, for example: following and observation in asymptomatic and uncomplicated cases; surgical resection for unifocal extra-nodal manifestations or symptomatic spinal, cranial, or airway involvements; administration of corticosteroids in symptomatic nodal or cutaneous disease; radiotherapy, chemotherapy or immunomodulatory drugs such as thalidomide and rituximab for more severe cases with refractory, disseminated or lifethreatening manifestations (16). We chose a surgical approach for our patient considering her unifocal cutaneous manifestation without any systematic involvement or lymphadenopathies. After the nodule excision, she was followed for almost six months, and no refractory or relapsed lesion of RDD was observed, and the patient was symptom-free.
As mentioned, CRDD has a favorable prognosis, but careful evaluations must carry on to distinguish it from its differential diagnoses especially Langerhans cell histiocytosis which is a rare and lethal disease, cutaneous lymphoma and other neoplastic histiocytosis (17). It is essential to perform a comprehensive clinical evaluation along with a thorough immunohistochemical study to diagnose RDD. Some histopathologic features are characteristic for RDD, including typical large histiocytes with contoured hypochromic nuclei and distinct round nucleoli in an abundant, pale, wispy cytoplasm; the presence of emperipolesis phenomenon in histocytes which is the engulfment of intact hematolymphoid and inflammatory cells; and a heterogeneous background of lymphocytes, plasma cells, micro abscess of neutrophils in the absence of eosinophils. Typically, in RDD immunohistochemistry, staining is positive for S100, CD68, CD163, CD14 and negative for CD1a and CD207 (8,14). All these characteristic features, in correlation with clinical presentations, help to distinguish between RDD and other diagnoses, for instance, Langerhans cell histiocytosis, as the most important differential diagnosis for CRDD is positive for CD1a and CD207, has eosinophilic infiltrate, and characteristic features like elongated grooved nuclei and Birbeck granules (18). Other differential diagnoses such as histiocytosis lymphoma, eruptive xanthoma, juvenile xanthogranuloma, and IgG4 related sclerosing disease could also be excluded by immunohistochemical features, clinical and serological evaluations (18,19). The histopathology of isolated CRDD and systematic CRDD with lymph node involvement are the same, however, some studies suggest CRDD has greater degree of fibrosis, sclerosis, and fewer histocytes with more subtle emperipolesis (18,20).
In conclusion We presented a patient with an isolated ulcerative dermal-based lesion that had typical cytomorphologic and immunohistochemical features for pure CRDD without any systematic presentation. Thus, the diagnosis of CRDD was confirmed for her condition.